Throughout and within this disclosure, various publications are referenced by first author and date, patent number or publication number. The full bibliographic citation for each reference can be found within the specification. The disclosures of these publications are hereby incorporated by reference into this disclosure to more fully describe the state of the art to which this invention pertains.
Resistance to chemotherapeutic treatments for cancer is a major health care problem. Resistance mechanisms can be classified as two types: endogenous and acquired. In cancer most drug resistance is enzyme mediated. Either the target enzyme is expressed at too high a level for the chemotherapeutic to block its activity without unacceptable toxicity to the host; or, alternatively, an enzyme is expressed by the diseased cell which rapidly modifies the chemotherapeutic, thereby abolishing its therapeutic activity. Endogenous resistance to chemotherapy can occur in cancer when the diseased cell loses tumor suppressor gene function (p53, RB, p16). When this occurs, enzymes such as thymidylate synthase (TS) and dihydrofolate reductase (DHFR) are expressed constitutively throughout the cell cycle (Yeager and Reznikoff (1998) J. Urol. 159 (2): 581-5; el-Deiry (1997) Curr. Opin. Oncol. 9 (1): 79-87; Goker, Waltham, et al. (1995) Blood 86(2):677-84; Banerjee, Ercikan-Abali, et al. (1995) Acta Biochem Pol. 42 (4): 457-64); Fan and Bertino (1997) Oncogene 14(10): 1191-1200; Slansky and Farnham (1996) Bioessays 18(1):55-62; Lenz, Danenberg, et al. (1998) Clin. Cancer Res. 4(5):1227-34; and Lee, et al. (1997) Exp. Cell Res. 234 (2): 270-6.) This results in increased endogenous resistance to the fluoropyrimidines (via elevated expression of TS) or to methotrexate (via elevated expression of DHFR). Approaches to new therapeutics have been largely limited to development of better enzyme inhibitors, or the search for new enzymes to inhibit (Hu, et al. (1998) J. Pharm. Sci. 87(7):886-90; Drake, et al. (1996) Biochem. Pharmacol. 51(10):1349-55; Schultz, et al. (1999) Anticancer Res. 19 (1A): 437-43; Touroutoglou and Pazdur (1996) Clin. Cancer. Res 2(2):227-43; and Handfield and Levesque (1999) FEMS Microbiol. Rev. 23(1):69-91). Applicants have developed a novel approach to development of therapeutics targeting well characterized enzymes. This technology is distinct from prior and historical approaches to cancer therapy and is referred to as “ECTA,” for Enzyme Catalyzed Therapeutic Activation.